Examination of the Evidence for Off-Label Use of Gabapentin

OBJECTIVES: (1) Describe the relevance of off-label use of gabapentin to managed care pharmacy; (2) summarize recent FDA warnings and media reports related to off-label gabapentin use; (3) review medical information pertaining to the off-label use of gabapentin; (4) outline alternatives to off-label use of gabapentin in an evidence-based fashion, where literature exists to support such alternatives; and (5) encourage key clinicians and decision makers in managed care pharmacy to develop and support programs that restrict the use of gabapentin to specific evidence-based situations. SUMMARY: Gabapentin is approved by the U.S. Food and Drug Administration (FDA) for adjunctive therapy in treatment of partial seizures and postherpetic neuralgia. Various off-label (unapproved) uses have been reported, and the use of gabapentin for off-label purposes has reportedly exceeded use for FDA approved indications. Pharmaceutical marketing practices and physician dissatisfaction with currently available pharmacological treatment options may be key factors that contribute to this prescribing trend. Recently, the media has focused on these issues, noting that many cases of reported safety and effectiveness of gabapentin for off-label use may have been fabricated. A thorough review of the medical and pharmacy literature related to off-label use of gabapentin was performed, and a summary of the literature for the following conditions is presented: bipolar disorder, peripheral neuropathy, diabetic neuropathy, complex regional pain syndrome, attention deficit disorder, restless legs syndrome, trigeminal neuralgia, periodic limb movement disorder of sleep, migraine headaches, and alcohol withdrawal syndrome. A common theme in the medical literature for gabapentin is the prevalence of open-label studies and a lack of randomized controlled clinical trials for all but a small number of indications. CONCLUSIONS: In the majority of circumstances where it has reported potential for off-label use, gabapentin is not the optimal treatment. The off-label use of gabapentin for indications not approved by the FDA should be reserved for cases where there is solid research support (e.g., diabetic neuropathy and prophylaxis of frequent migraine headaches). Managed care pharmacists should develop programs to restrict the use of gabapentin to these specific evidence-based situations, and key decision makers in managed care practice should feel confident in supporting these use restrictions for gabapentin.

label conditions; company medical science liaisons were also alleged to have been involved in this practice. 4 The authors of one news article noted that many reported cases of safety and effectiveness with unapproved use of the drug appeared to be fabricated by the manufacturer.
A follow-up story in January 2003 about a "whistle-blower" lawsuit related to allegedly illegal marketing practices included an explanation of some of the issues, with particular emphasis on the clinically inappropriate promotion of gabapentin for bipolar disorder. 4 The lawsuit involves charges made by a for-   mer salesman that the company used a systematic strategy to promote gabapentin for various off-label uses. The extension of potential uses of gabapentin contributed to the drug' s tremendous financial success, essentially creating a "blockbuster" drug in terms of sales. In 2000 alone, gabapentin earned $1.3 billion in sales, and as much as 78% of these sales were for uses without clinical evidence of safety or effectiveness. 4

II Review of the Clinical Literature
Off-label use of gabapentin has been reported in bipolar disorder, peripheral neuropathy, diabetic neuropathy, complex regional pain syndrome, attention deficit disorder, restless legs syndrome, trigeminal neuralgia, periodic limb movement disorder of sleep, migraine headaches, and drug and alcohol withdrawal syndrome. A recurring theme in the literature, with the exception of neuropathic pain and migraine, is a prevalence of open-label studies with a lack of randomized controlled clinical trials. It is important to consider that an inherent problem with open-label trial design is the potential for introduction of bias because the treatment assignment is known.

Gabapentin in the Treatment of Bipolar Disorder
Extensive review confirms that current published literature on gabapentin is primarily based on open-label trials that evaluate small numbers of patients (Table 1). [8][9][10][11][12][13][14][15] The few randomized controlled trials designed to investigate the efficacy of gabapentin in treating bipolar disorder have concluded that there is no significant difference in the effects of the drug compared with placebo. 16,17 This supports the likelihood of bias in the various open-label studies since these results have not been confirmed in the randomized controlled trials. Various authors of medical reviews on this subject have concluded that gabapentin should not be recommended for treatment of bipolar disorder and that double-blind, randomized controlled trials are needed to confirm any true efficacy of the drug in management of this condition. [18][19][20][21] Real-life practice involves instances of refractory bipolar disorder that exhaust the current treatment options. The Texas Medication Algorithm Project (TMAP) lists lamotrigine or gabapentin only as salvage therapy. Therefore, these 2 agents should be reserved for unstable patients at the seventh stage of treatment in hypomanic/manic episodes. 22 In all other forms of bipolar disorder, gabapentin is not recommended at any phase of therapy.
Although limited comparative data are available on the subject, results from a cross-over study suggest that lamotrigine may be superior to gabapentin as well as placebo for the management of refractory mood disorders. 23 The investigators studied 31 patients who had either bipolar I, bipolar II, or unipolar disorder and failures of other mood stabilizing agents. Lamotrigine was titrated to 300 mg-500 mg by weeks 5 and 6, and gabapentin was titrated to 4,800 mg daily by week 6. At week 6, based on the Clinical Global Impression Score, 52% of patients responded to lamotrigine, 26% responded to gabapentin, and 23% responded to placebo (P=0.011, lamotrigine versus gabapentin). The results of this study suggest that lamotrigine might be considered in cases of treatment refractory to first-line agents in bipolar disorder.

Gabapentin in the Treatment of Pain Syndromes, Peripheral Neuropathy, and Diabetic Neuropathy
The exact mechanism of action of gabapentin in managing neuropathic pain is unknown; however, it is speculated to work via  voltage-activated calcium ion channels at the postsynaptic dorsal horn, thereby interrupting the series of events that leads to the sensation of neuropathic pain. Review of the various hypotheses concerning these pharmacologic theories is beyond the scope of this article but may be found elsewhere. [24][25][26] While the clinical literature in support of gabapentin use for conditions of neuropathic pain is more favorable than that concerning its use in various other disease states, there remain issues concerning its merits in clinical practice. These involve variable doses, few direct comparisons to other agents, and, again, a number of open-label studies with the potential for bias. Nonetheless, gabapentin does have proven efficacy for the treatment of diabetic neuropathy and postherpetic neuralgia. 32,33 A summary of selected published studies on this subject appears in Table 2. [27][28][29][30][31][32][33] Morello et al. demonstrated that there is no statistically significant difference between amitriptyline and gabapentin in the treatment of diabetics with peripheral neuropathic pain, as measured by pain scales and global pain scores. 34 In this study, 21 diabetic patients with stable glycemic control received either gabapentin or amitriptyline for 6 weeks and then crossed over to the other arm of therapy for 6 additional weeks, with a 1-week wash-out period between therapies. Dosage was adjusted based on the patient' s response, with a mean gabapentin dose of 1,565 mg and a mean amitriptyline dose of 59 mg. Both medications were found to significantly decrease pain scores from baseline (P<0.001). Sixty-seven percent of amitriptyline patients reported moderate or greater pain relief, and 52% of gabapentin patients reported such relief (P=0.26).
Current treatment guidelines favor using amitriptyline, nortriptyline, or gabapentin for the management of painful neuropathic conditions. It is recognized that, in specific clinical circumstances, the adverse-effect profile of the tricyclics may prove unacceptable, thus warranting consideration of therapeutic alternatives. However, in cases without tricyclic contraindications, cost should also be considered when selecting an initial option for treatment.
In the Morello study, 34 the agents were proven comparable in clinical efficacy. In fact, these authors suggested a slight advantage to using amitriptyline over gabapentin, although the difference was not statistically significant. Comparing prices of the agents given in doses for the management of neuropathic pain, amitriptyline and nortriptyline cost only a small fraction of the significant direct drug cost associated with gabapentin (Table 3). 35 Therefore, the tricyclics appear to offer a lower-cost therapeutically equivalent alternative to gabapentin in many situations.

Gabapentin in the Treatment of Complex Regional Pain Syndrome
There are no reports that confirm efficacy of gabapentin in management of complex regional pain syndrome, also known as reflex sympathetic dystrophy (RSD). The literature is sparse and primarily anecdotal in nature, composed of 2 reports involving a total of 7 patients in addition to 2 letters ( Table 4) that offer little scientific value. [36][37][38][39][40] From an evidence-based standpoint, the available information is insufficient to support use of gabapentin in this condition. Recognized medical treatments for RSD include adrenergic blockers, nonsteroidal antiinflammatory drugs, calcium channel blockers, phenytoin, opioids, and calcitonin. 39

Gabapentin in the Treatment of Attention Deficit Disorder
There are 3 published reports related to behavioral disturbances and the use of gabapentin, none of which were clinical trials. One case report is specific to the use of the drug in attention deficit hyperactivity disorder (ADHD). A second case report involved 7 patients who experienced behavioral side effects with gabapentin. The third citation was a letter (Table 5). [41][42][43] Thus, the evidence related to the use of gabapentin in ADHD is insufficient to warrant its use for this condition.
Stimulants have been the mainstay of ADHD therapy for decades, but there is a rising trend in pediatric polypsychopharmacy with little or no research to support this phenomenon. 44 Since there is no evidence to support the use of gabapentin in ADHD, alternative clinically appropriate and supportable treatment options should be given primary consideration when formulating treatment plans for cases refractory to stimulants in ADHD. Current treatment guidelines suggest a trial with a stimulant along with diet, behavior management, special education, and perhaps psychotherapy in ADHD disease management. 43 Published Reports Related to Use of Gabapentin in Complex Regional Pain Syndrome I

Gabapentin in the Treatment of Restless Leg Syndrome
Restless leg syndrome (RLS) is an awake phenomenon characterized by an intense, irresistible urge to move the legs, usually associated with sensory complaints, motor restlessness, worsening of symptoms at rest and relief with motor activation, and increased severity in the evening or during the night. Sparse case reports have suggested potential use of gabapentin in RLS, but, again, there are no controlled clinical trials that assess its safety and effectiveness in treatment of this condition. [45][46][47][48][49] The Standards of Practice Committee of the American Academy of Sleep Medicine (AASM), in conjunction with specialists and other interested parties, developed guidelines for managing RLS that were subsequently approved by the Board of Directors of AASM. The recommendations were identified as standards, guidelines, or options, based on the strength of evidence from published studies that meet criteria for inclusion ( Table 6).
The AASM guideline classifies the following agents as having sufficient evidence to support their use in RLS treatment: (1) levodopa with decarboxylase inhibitor and pergolide, (2) oxycodone and propoxyphene, or (3) carbamazepine. AASM has reported that the dopaminergic agents are notably the best studied and most successful agents for the treatment of RLS. 50 Alternatively, they have commented that gabapentin has limited "Level V" evidence (case-series reports only), consisting of only 2 case studies. For this reason, AASM has classified use of gabapentin in RLS as a patient-care strategy that reflects uncertain clinical use. The members of the panel felt that there is inconclusive data, conflicting evidence, or conflicting expert opinion on the use of gabapentin for managing RLS. 50

Gabapentin in the Treatment of Trigeminal Neuralgia
Conclusive studies confirming the efficacy of gabapentin in the treatment of trigeminal neuralgia are lacking. To date, literature supporting the effectiveness of gabapentin in trigeminal neuralgia is limited to case studies in aggregate of less than 30 patients. [51][52][53] Carbamazepine remains the drug of first choice. 54 If paroxysms of pain still occur with therapeutic blood levels, phenytoin or baclofen should be added. 54 Lamotrigine was recently validated for use in refractory trigeminal neuralgia, especially due to multiple sclerosis. 51,52,55 Gabapentin in the Treatment of Periodic Limb Movement Disorder of Sleep Periodic limb movements of sleep occur as an asleep phenomenon and are characterized by periodic episodes of repetitive and highly stereotyped limb movements. These patients typically have complaints of insomnia or excessive sleepiness with no other disorder to explain the symptoms.
RLS and periodic limb movement disorder (PLMD) of sleep are distinct disorders by definition, but they have been reported to coexist in approximately 80% of cases. However, the treatment of the 2 conditions is not always the same. There is no reference to the use of gabapentin in PLMD, and there is no mention of gabapentin in recommendations of AASM. 50 There is no published evidence demonstrating efficacy of gabapentin in the management of PLMD. Experts have reported that symptoms may respond to correction of a coexisting iron deficiency anemia or to treatment with dopaminergic medication (such as levodopa or bromocriptine), benzodiazepines (diazepam or clonazepam), or opiates (codeine, propoxyphene, or oxycodone). 56

Gabapentin in the Treatment of Migraine
Pharmacoeconomic analyses reveal that gabapentin is only cost effective for migraine prophylaxis in patients who experience very frequent migraine headaches. Adelman et al. studied the costs for acute migraine care following initiation of prophylactic medications. They reported that divalproex patients must have  (1):87-90. hyperactivity, and defiance. All behavioral changes were reversible and were managed by dose reduction or discontinuation of gabapentin. more than 10 migraine episodes per month while gabapentin patients must have more than 24 migraine episodes per month before these drugs can be considered cost effective. [57][58][59][60] While there are clinical trials of gabapentin in migraine prophylaxis, outstanding questions remain regarding the drug' s utility in clinical practice. One randomized, placebo-controlled study of 63 patients showed that gabapentin in daily prophylactic doses of 1,200 mg is well tolerated and reduces headache frequency and the use of drugs to produce symptomatic relief. 61 While gabapentin appeared to be effective in this particular trial, it is still unclear how gabapentin would compare to other more-established pharmacotherapy for migraine prophylaxis. Thus, gabapentin should be considered for use in migraine syndrome management only after failure of standard prophylaxis regimens (Table 7).

Gabapentin in the Treatment of Drug and Alcohol Withdrawal Seizures
Mayo-Smith published an evidence-based practice guideline for the pharmacological management of alcohol withdrawal. 62 He completed a meta-analysis of prospective controlled trials only, with methodologically sound endpoints (e.g., withdrawal severity, delirium, seizures, completion of withdrawal, entry into rehabilitation, adverse events) corresponding to the Diagnostic and Statistical Manual of Mental Disorders. Mayo-Smith concluded that benzodiazepines remain the gold standard for management of alcohol withdrawal and that dosage should be individualized based on withdrawal severity.
According to this analysis, the author notes that beta-blockers, clonidine, and carbamazepine may be considered as adjunctive therapy. 62 There was no mention of gabapentin in this guideline since published reports of gabapentin for these indications are limited to case reports, open-label studies, and anecdotal letters. [63][64][65][66][67] Thus, gabapentin cannot be recommended for use in any aspect of the management of alcohol withdrawal seizures, either as initial or add-on therapy.

II Conclusions
In the majority of circumstances where it has reported potential for indications not approved by the FDA (i.e., off-label use), gabapentin is not the optimal treatment. The reader should remain cautious regarding claims that gabapentin offers any benefit in treating conditions other than those with FDA approval. Hamer et al. concluded, "While case reports and open-label trials are valuable for directing further research, they are generally not sufficient as the basis of treatment decisions." Gabapentin is not recommended in the clinical guidelines or established treatment algorithms (e.g., American Academy of Neurology or AASM guidelines or TMAP algorithm) for any of the off-label indications. Considering the evidence, gabapentin should be used almost exclusively for the FDA-approved indications-treatment of seizures and postherpetic neuralgia.
Off-label use of gabapentin should be reserved for patients who have failed standard treatment options and in those cases where randomized controlled clinical trials have demonstrated gabapentin efficacy (i.e., diabetic neuropathy and migraine headaches). Costeffectiveness ratios tend to be high (unfavorable) for the use of gabapentin in diabetic neuropathy and migraine syndrome except in those patients who experience a high frequency of acute episodes.
Pharmaceutical manufacturer marketing practices appear to   be a key contributor to the use of gabapentin in excess of its scientifically proven value. One additional factor is the perceived need for treatment options among clinicians dissatisfied with currently available therapies. The financial success of gabapentin could be at least partially attributable to the placebo effect since the majority of the off-label conditions are associated with an underlying psychological component.

DISCLAIMER
Since various disease states are discussed in this review, it is essential to note that the references to treatment guidelines and algorithms are summary in nature and are in no way intended to replace the various expert consensus and more thorough reviews on the various subjects.

ACKNOWLEDGMENTS
The author would first like to acknowledge Robert Mack for his patience and encouragement throughout the process of developing and writing this manuscript. The author would also like to acknowledge the following individuals at Three Rivers Administrative Services, LLC: Warren Carmichael, CEO, for the opportunity to be a part of this organization and pursue this project; Robert Baker, MD, MMM, FAAP, senior medical director, for thoughtful comments that made a valuable contribution to this manuscript; Jessica Neely, PharmD, clinical pharmacist; and Jim Hancovsky, RPh, MSIA, pharmacy director, for helpful review of an earlier version of this manuscript.

DISCLOSURES
No outside funding supported this study. The author discloses that she has no financial affiliation with or interest in any company, product, or service that is discussed in this article.